The long-term goal of this research is to understand the molecular mechanisms underlying the phenotypes seen in Down syndrome (DS). DS, due to partial or full trisomy of chromosome 21, is the most common aneuploidy and affects approximately 1 in 700 live births in all ethnic groups. DS patients have numerous clinical problems including mental retardation, congenital heart defects, hypotonia and early onset Alzheimer's disease (AD), but the causes of these phenotypic features are not clearly understood. The Down syndrome critical region 1 (DSCR1) gene, located on chromosome 21, is up-regulated in fetal DS brain and encodes an inhibitor of calcineurin. Using Drosophila as a model system, we have previously shown that the Drosophila homolog of human DSCR1, nebula, is crucial for learning and memory. Recently we discovered that nebula also interacts with a mitochondrial protein, the adenine nucleotide translocator (ANT), and influences its activity. Furthermore, we found that nebula is required for normal mitochondrial function and maintenance of mitochondrial integrity. These results, together with reports showing mitochondrial dysfunction in DS and AD, lead us to hypothesize that abnormal expression of nebula/DSCR1 in DS causes mitochondrial dysfunction and subsequent adverse effects on normal cell function, leading to increased susceptibility to AD. To address these hypotheses, we propose the following Specific Aims: 1) To determine the physiological consequences of abnormal mitochondrial function due to nebula mutations. 2) To identify genes regulating nebula localization and function in mitochondria. 3) To investigate whether nebula/DSCR1 over-expression increases susceptibility to developing pathological features of AD. [unreadable] [unreadable] [unreadable]